Defining the role of migratory dendritic cells in priming T cells to mycobacteria
Author: Krmeská, Veronika
Date: 2022-06-08
Location: Inghesalen, Karolinska Institutet, Solna
Time: 13.00
Department: Inst för mikrobiologi, tumör- och cellbiologi / Dept of Microbiology, Tumor and Cell Biology
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Thesis (1.883Mb)
Abstract
Dendritic cells (DCs) are professional antigen-presenting cells that bridge innate and adaptive immunity by priming T cells. DCs residing at body surfaces such as skin sense invading microbes and respond by internalizing the microbe at the site of infection and subsequently migrating to the draining lymph node (dLN) where they present microbial antigen and other requisite signals to T cells that arm the T cells to fight-off the infection. The mobilization of DCs from skin to dLN remains incompletely understood in the context of infection. The studies in this thesis investigate the relocation of skin DCs to dLN after skin infection with two model microorganisms and live attenuated vaccines, Mycobacterium bovis Bacille Calmette-Guérin (BCG) and Vaccinia virus (VACV).
Using a mouse model of BCG skin infection and a fluorochrome-based assay to track skin DC migration to dLN, we found that cyclooxygenase (COX)-2-derived prostaglandin E2 (PGE2) contributes to DC migration in response to BCG. Having previously shown in this same model that IL-1 was important for BCG-triggered skin DC migration, it was unexpected that the COX/PGE2 pathway of migration was invoked independently of IL-1. In addition, the COX/PGE2 pathway was only active in response to viable bacilli. Furthermore, skin DC migration, the accompanying transport of BCG bacilli and priming of antigen-specific CD4+ T cells in dLN were strongly dependent on the BCG inoculation dose in the skin. Interestingly, BCG dose was more important in driving the overall number of skin DCs reaching the dLN than in eliciting a dose-escalating effect on DC expression of co-stimulatory molecules or MHC-II.
In stark contrast to BCG, skin DCs did not relocate to dLN in response to VACV. Rather, VACV seems to actively block DC migration from the site of infection. This suppressive effect of VACV was capable of mitigating responses to a subsequent challenge with BCG in the skin, impairing skin DC migration and BCG transport to dLN, and delaying CD4+ T cell priming in the dLN.
Using a mouse model of BCG skin infection and a fluorochrome-based assay to track skin DC migration to dLN, we found that cyclooxygenase (COX)-2-derived prostaglandin E2 (PGE2) contributes to DC migration in response to BCG. Having previously shown in this same model that IL-1 was important for BCG-triggered skin DC migration, it was unexpected that the COX/PGE2 pathway of migration was invoked independently of IL-1. In addition, the COX/PGE2 pathway was only active in response to viable bacilli. Furthermore, skin DC migration, the accompanying transport of BCG bacilli and priming of antigen-specific CD4+ T cells in dLN were strongly dependent on the BCG inoculation dose in the skin. Interestingly, BCG dose was more important in driving the overall number of skin DCs reaching the dLN than in eliciting a dose-escalating effect on DC expression of co-stimulatory molecules or MHC-II.
In stark contrast to BCG, skin DCs did not relocate to dLN in response to VACV. Rather, VACV seems to actively block DC migration from the site of infection. This suppressive effect of VACV was capable of mitigating responses to a subsequent challenge with BCG in the skin, impairing skin DC migration and BCG transport to dLN, and delaying CD4+ T cell priming in the dLN.
List of papers:
I. Veronika Krmeská, Juliana Bernardi Aggio, Susanne Nylén, Pryscilla Fanini Wowk, Antonio Gigliotti Rothfuchs. Cyclooxygenase-derived prostaglandin E2 drives IL-1-independent Mycobacterium bovis Bacille Calmette-Guérin-triggered skin Dendritic cell migration to draining lymph node. JOURNAL OF IMMUNOLOGY. 2022. [Accepted]
Fulltext (DOI)
Pubmed
II. Veronika Krmeská, Lei Shen, Nuno Rufino de Sousa, Susanne Nylén, Pryscilla Fanini Wowk, Antonio Gigliotti Rothfuchs. BCG infection dose guides Dendritic cell migration and T-cell priming in the draining lymph node. [Manuscript]
III. Juliana Bernardi Aggio, Veronika Krmeská, Brian J. Ferguson, Pryscilla Fanini Wowk, Antonio Gigliotti Rothfuchs. Vaccinia virus infection inhibits skin Dendritic cell migration to the draining lymph node. JOURNAL OF IMMUNOLOGY. 2021, 206: 776-784.
Fulltext (DOI)
Pubmed
View record in Web of Science®
I. Veronika Krmeská, Juliana Bernardi Aggio, Susanne Nylén, Pryscilla Fanini Wowk, Antonio Gigliotti Rothfuchs. Cyclooxygenase-derived prostaglandin E2 drives IL-1-independent Mycobacterium bovis Bacille Calmette-Guérin-triggered skin Dendritic cell migration to draining lymph node. JOURNAL OF IMMUNOLOGY. 2022. [Accepted]
Fulltext (DOI)
Pubmed
II. Veronika Krmeská, Lei Shen, Nuno Rufino de Sousa, Susanne Nylén, Pryscilla Fanini Wowk, Antonio Gigliotti Rothfuchs. BCG infection dose guides Dendritic cell migration and T-cell priming in the draining lymph node. [Manuscript]
III. Juliana Bernardi Aggio, Veronika Krmeská, Brian J. Ferguson, Pryscilla Fanini Wowk, Antonio Gigliotti Rothfuchs. Vaccinia virus infection inhibits skin Dendritic cell migration to the draining lymph node. JOURNAL OF IMMUNOLOGY. 2021, 206: 776-784.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Rothfuchs, Antonio
Co-supervisor: Nylén, Susanne; Rottenberg, Martin; Ferguson, Brian
Issue date: 2022-05-16
Rights:
Publication year: 2022
ISBN: 978-91-8016-545-7
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